Platelet-derived growth factor C (PDGF-C), a novel growth factor that binds to PDGF alpha and beta receptor.

We have characterized platelet-derived growth factor (PDGF) C, a novel growth factor belonging to the PDGF family. PDGF-C is a multidomain protein with the N-terminal region homologous to the extracellular CUB domain of neuropilin-1, and the C-terminal region consists of a growth factor domain (GFD) with homology to vascular endothelial growth factor (25%) and PDGF A-chain (23%). A serum-sensitive cleavage site between the two domains allows release of the GFD from the CUB domain. Competition binding and immunoprecipitation studies on cells bearing both PDGF alpha and beta receptors reveal a high affinity binding of recombinant GFD (PDGF-CC) to PDGF receptor-alpha homodimers and PDGF receptor-alpha/beta heterodimers. PDGF-CC exhibits greater mitogenic potency than PDGF-AA and comparable or greater mitogenic activity than PDGF-AB and PDGF-BB on several mesenchymal cell types. Analysis of PDGF-CC in vivo in a diabetic mouse model of delayed wound healing showed that PDGF-CC significantly enhanced repair of a full-thickness skin excision. Together, these studies describe a third member of the PDGF family (PDGF-C) as a potent mitogen for cells of mesenchymal origin in in vitro and in vivo systems with a binding pattern similar to PDGF-AB.

Infection with hepatitis A and TT viruses and socioeconomic status in Rio de Janeiro, Brazil.

The prevalence of antibodies directed against the enterically transmitted hepatitis A virus (HAV) was measured in 2 groups of people living in Rio de Janeiro, Brazil. Of 1,056 health care workers (HCWs), 778 (73.7%) were anti-HAV positive. A high prevalence of anti-HAV antibodies (85.7%) was also found among 274 voluntary blood donors (BDs). TT virus (TTV) is a DNA virus that has been found in the sera of patients with post-transfusion hepatitis of unknown etiology. Occurrence of virus shedding suggests that the fecal-oral route may be an important mode of TTV transmission, particularly in the developing world. The presence of TTV DNA was analyzed by PCR in the sera of 191 HCWs and 151 BDs. TTV was detected in 65.4% of HCWs and 79.5% of BDs. In both groups, a family income of < US$400 per month and a level of education of < 11 y of schooling were found to be risk factors for HAV infection. Furthermore, a low family income was associated with TTV viremia in the HCW group. However, the presence of TTV DNA was associated with neither low level of education nor anti-HAV positivity.

52-Week oral gavage chronic toxicity study with ubiquinone in rats with a 4-week recovery.

Potential ubiquinone (CoQ10; a natural fermentation product) toxicity was assessed in rats administered CoQ(10) by oral gavage for 1 year at 100, 300, 600, and 1200 mg/(kg day). No adverse changes in mortality, clinical signs, body weight, food consumption, or clinical pathology results occurred. CoQ(10) had elimination half-lives ranging from 10.7 to 15.2 h. At 1200 mg/(kg day), a high incidence of orange, granular, lumenal exudate in nasal turbinates occurred; microscopically, findings similar to those in the turbinates were occasionally observed in small granulomas within lung alveoli. A dose-related increased incidence of vacuolated macrophages (mesenteric lymph nodes) and vacuolated hepatic periportal cells was noted. Neither were associated with tissue damage or organ dysfunction, so they were not considered to be adverse. The nasal turbinate and lung findings were probably secondary to incidental exposure to crystallized test material. Overall, CoQ(10) was well tolerated by male and female rats at dose levels up to 1200 mg/(kg day).

Randomized clinical outcome study of critically ill patients given glutamine-supplemented enteral nutrition.

Glutamine is normally an abundant amino acid in the body. It has many important metabolic roles, which may protect or promote tissue integrity and enhance the immune system. Low plasma and tissue levels of glutamine in the critically ill suggest that demand may exceed endogenous supply. A relative deficiency of glutamine could compromise recovery, resulting in prolonged illness and an increase in late mortality, morbidity, and consequently hospital costs. Using a prospective block-randomized, double-blind treatment study design, we tested whether a glutamine-containing enteral feed compared with an isonitrogenous, isoenergetic control feed would influence outcome. The study endpoints were morbidity, mortality, and hospital cost at 6 mo postintervention. In one general intensive care unit (ICU), to ensure consistency of management policies, 78 critically ill adult patients with Acute Physiological and Chronic Health Evaluation (APACHE) II score of 11 and greater and who were considered able to tolerate introduction of enteral nutrition were studied. Fifty patients successfully received enteral nutrition (26 glutamine, 24 control). There was no mortality difference between those patients receiving glutamine-containing enteral feed and the controls. However, there was a significant reduction in the median postintervention ICU and hospital patient costs in the glutamine recipients $23,000 versus $30,900 in the control patients (P = 0.036). For patients given glutamine there was a reduced cost per survivor of 30%. We conclude that in critically ill ICU patients enteral feeds containing glutamine have significant hospital cost benefits.

Internet teleconferencing as a clinical tool for anesthesiologists.

Internet teleconferencing software can be used to hold "virtual" meetings, during which participants around the world can share ideas. A core group of anesthetic medical practitioners, largely consisting of the Society for Advanced Telecommunications in Anesthesia (SATA), has begun to hold regularly scheduled "virtual grand rounds." This paper examines currently available software and offers impressions of our own early experiences with this technology. Two teleconferencing systems have been used: White Pine Software CU-SeeMe and Microsoft NetMeeting. While both provided acceptable results, each had specific advantages and disadvantages. CU-SeeMe is easier to use when conferences include more than two participants. NetMeeting provides higher quality audio and video signals under crowded network conditions, and is better for conferences with only two participants. While some effort is necessary to get these teleconferencing systems to work well, we have been using desktop conferencing for six months to hold virtual Internet meetings. The sound and video images produced by Internet teleconferencing software are inferior to dedicated point-to-point teleconferencing systems. However, low cost, wide availability, and ease of use make this technology a potentially valuable tool for clinicians and researchers.

Microvascular endothelial activation in the skeletal muscles of patients with multiple organ failure.

The relationship between microvascular damage and the presence of muscle fibre atrophy and necrosis has been investigated in skeletal muscle biopsies taken from 57 patients with multiple organ failure. Immunohistochemical studies showed no loss of capillaries and no luminal thrombosis, while neutrophil leucocytes were more prevalent in the patients' biopsies than in controls. Deposition of the complement membrane attack complex (C5-9MAC) in capillaries was observed in 41% of cases. Endothelial activation was suggested by an increased intensity of expression of ICAM-1, and by an increased proportion of capillaries expressing P selectin and E selectin, although this was not directly associated with neutrophil accumulation. Endothelial swelling was present in many biopsies with 38% of the biopsies having larger capillary profiles on immunohistochemical labelling for von Willebrand factor (vWF), thrombomodulin and CD34, and on Ulex europaeus agglutinin 1 binding. Endothelial swelling was confirmed by image analysis and morphometric evaluation of capillary ultrastructure, however, the capillary luminal area was not reduced as the capillaries were dilated. Increased vWF labelling was associated with C5-9MAC deposition and with fibre necrosis, but the vascular changes were not related to fibre atrophy nor to clinical indices of the severity of the patients' illness. The results suggest that microvascular damage and ischaemia may not be major factors in the pathogenesis of muscle fibre damage in multiple organ failure, but that endothelial activation is a common occurrence. The variability in the patterns of markers of endothelial activation, and the small proportion of capillaries affected, may reflect the complexity of the endothelial response to circulating or locally produced cytokines.

Sucrose acetate isobutyrate (SAIB): three-generation reproduction study in the rat and teratology studies in the rat and rabbit.

A three-generation reproduction study of sucrose acetate isobutyrate (SAIB) in Fischer 344 rats and teratology studies in Fischer 344 rats and New Zealand white rabbits were performed. Dietary SAIB concentrations to provide dose levels of 0, 0.5, 1.0 and 2.0 g/kg body weight were used for the rat studies, and 0, 0.5, 0.85 and 1.2 g/kg body weight doses of SAIB in corn oil were administered by gavage in the rabbit studies. F0 generation male rats were fed SAIB for 10 wk, and female rats were fed SAIB for 2 wk prior to mating. F1 generation rats were raised on the test diets to maturity, mated to produce F2a litters, and remated to produce the F2b litters that were examined for teratology. F2a rats were mated to study fertility indices for the F3 pregnancy. A decrease in female fertility compared with controls was noted at the highest dose of SAIB during breeding of the F1 generation to produce the F2a litters. No difference in fertility rate between controls and treated animals was noted in the results of the other three matings that were performed, and it was concluded that the reduction in female fertility was not related to SAIB treatment. No morphological abnormalities of soft tissue or skeleton were observed in the rat or rabbit teratology studies. The highest dose levels administered, 2.0 g SAIB/kg body weight in the rat and 1.2 g SAIB/kg body weight in the rabbit, were considered to be no-observed-adverse effect levels (NOAEL).

Muscle fibre atrophy in critically ill patients is associated with the loss of myosin filaments and the presence of lysosomal enzymes and ubiquitin.

Muscle wasting and weakness are common features of patients with critical illnesses, and may impair their recovery. This study examines whether cytoskeletal and contractile proteins are damaged, and which proteolytic mechanisms might be involved, in the muscle fibre atrophy or necrosis associated with the acute myopathy of critically ill patients. Ninety-eight muscle biopsies were obtained by the conchotome method from 57 critically ill patients and examined morphometrically and by immunohistochemical labelling. Sequential biopsies showed a mean reduction in fibre cross-sectional areas of 3-4% per day. More intense immunolabelling for desmin was seen in the smaller fibres of 52% of the biopsies, while immunolabelling for dystrophin, actin and myosin heavy chains was maintained. Myosin ATPase activity was weak in the smaller fibres in some biopsies, and electron microscopy showed the loss of myosin filaments in atrophic fibres. These changes suggest that loss of the filamentous structure of myosin, without degradation of the immunolabelled epitopes, leads to the collapse of the intermyofibrillar desmin network. Fibres with abnormal desmin labelling showed increased cathepsin B, lysozyme and ubiquitin immunolabelling. Nine cases showed increased immunolabelling for heat shock protein 72. The changes in desmin immunolabelling were more prevalent in patients with higher APACHE II scores on admission, but were not related to other clinical features. The results indicate that fibre atrophy is associated with myosin filament depolymerization and the presence of several proteolytic enzymes. In our study, these changes occurred in patients who were critically ill but who did not receive large doses of steroids or neuromuscular blocking agents.

Six-month outcome of critically ill patients given glutamine-supplemented parenteral nutrition.

An abundant amino acid in the human body, glutamine (Gln) has many important metabolic roles that may protect or promote tissue integrity and enhance the immune system. Low plasma and tissue levels of Gln in the critically ill suggest that demand may exceed endogenous supply. A relative deficiency of Gln in such patients could compromise recovery and result in prolonged illness and an increase in late mortality. This study examines this hypothesis. Using a prospective, block-randomized, double-blind treatment study design, we tested whether a Gln-containing parenteral nutrition (PN) compared with an isonitrogenous, isoenergetic control feed would influence outcome, with the endpoints of morbidity, mortality, and cost at 6 mo postintervention. In one general intensive care unit (ICU), to ensure consistency of management policies, 84 critically ill adult patients, with Acute Physiological and Chronic Health Evaluation II score > 10, requiring nutritional support received PN only if enteral nutrition was contraindicated or unsuccessful. Survival at 6 mo was significantly improved in those receiving Gln PN (24/42 versus 14/42; P = 0.049). Significantly more deaths occurred in patients requiring control PN for > 10 d (P = 0.03). The excess control deaths occurred later and those patients had had a significantly longer postintervention stay (P = 0.012) and use of ICU. In the Gln recipients, the total ICU and hospital cost per survivor was reduced by 50%. In critically ill ICU patients unable to receive enteral nutrition, a Gln-containing PN solution improves survival at 6 mo and reduces the hospital costs per survivor.

WCALive: broadcasting a major medical conference on the Internet.

Live video and sound from the 11th World Congress of Anaesthesiology in Sydney, Australia were broadcast over the Internet using the CuSeeme software package as part of an ongoing evaluation of Internet-based telecommunication in the delivery of Continuing Medical Education (CME). This was the first time such a broadcast had been attempted from a medical convention. The broadcast lasted for four days, during which a functioning combination of computer hardware and software was established. Technical issues relating to broadcast of these real time signals over ISDN links and the Internet itself were addressed. Over 200 anaesthetists from around the world were able to 'attend' the plenary sessions via the Internet. Evidenced by feedback received audio reception was quite good. Video reception was less successful for those receiving the broadcast via a modem based Internet connection. The received signal in such circumstances was adequate to provide a video presence of the speaker but inadequate to allow details of 35 mm slides to be visualised. We conclude that this technology will be of use in the delivery of CME materials to remote areas provided simultaneous viewing of high resolution still images is possible using another medium, such as the World Wide Web.

Parenteral glutamine supply in intensive care patients.

Glutamine, an abundant amino acid, has many metabolic roles that protect tissue integrity and enhance the immune system. Low plasma and tissue levels of glutamine in the critically-ill suggest that demand may exceed endogenous supply and with the profound muscle wasting that occurs this supply of glutamine may become critical to survival. The very sickest patients who are unable to tolerate enteral feeding are solely dependent on conventional parenteral nutrition which does not contain glutamine. This short review, drawing upon a recent double blind randomised clinical six month outcome study, provides the rationale to suggest that parenteral glutamine supply in these very sick patients may improve recovery and reduce late mortality.

Effect of parenteral L-glutamine on muscle in the very severely ill.

Glutamine (Gln)-supplemented perioperative total parenteral nutrition (TPN) has been reported to reduce the loss of intramuscular glutamine following routine surgery. This study investigates whether glutamine-supplemented TPN can alter muscle biochemistry acutely in the very severely ill patient. Thirty-eight patients (age 19-77 yr; mean 55 yr), critically ill (APACHE II range 8-31; median 17) admitted to the intensive care unit (ICU) were recruited to receive either conventional TPN (CTPN) or an isonitrogenous, isoenergetic feed supplemented with 25 g crystalline L-glutamine per 24 h (GTPN) in a prospective, double blind, block-randomized study. In a representative sample of these patients, relatives consented to a paired muscle biopsy taken before feeding (10 GTPN/9 CTPN patients; ICU Day 2-4) and repeated 5 days later (16 patients; ICU Day 7-9). Muscle biopsies and matching plasma samples were analyzed using a coupled glutaminase-glutamate dehydrogenase enzymatic assay. A correction was made using sodium to account for the massive changes in extracellular fluid volume. The average muscle Gln content before feeding was very low. Between biopsies no consistent pattern of change was seen with or without exogenous Gln. It also proved difficult in these very sick patients to correct a low plasma Gln with L-Gln-TPN during the initial phase of the severe illness. TPN supplementation with 25 g/24 h, L-glutamine appears inadequate in the acute period to counteract the muscle and plasma biochemical changes seen in these patients. It is unknown whether any larger dose could alter this state.

Effect of passive stretching on the wasting of muscle in the critically ill.

This study examine whether muscle wasting in critically ill patients can be prevented by passive stretching alone in the absence of contractile activity. Five critically ill patients who required a complete neuromuscular blockade for 7 days of ventilator support were studied. One leg of each patient was treated with continuous passive motion (CPM) for three 3-h periods daily while the other leg received only routine nursing care. Fiber atrophy was prevented in the more severely ill patients and there was a slight gain in fiber area (mean increase, +11%) in the CPM limb compared with the control leg, which decreased (mean decrease, -35%) over 7 days. Fiber area was preserved in both fiber types but was more pronounced in type I muscle fibers. Protein loss was significantly less in the CPM limb. There was a significantly greater increase in wet weight per mg DNA in the control limb. However, as an index of wasting, the ratio of protein to DNA decreased similarly in both limbs. Passive stretching can preserve the architecture of muscle fibers. Whether it can prevent muscle wasting remains uncertain.

Toxicity of the protein kinase C inhibitor safingol administered alone and in combination with chemotherapeutic agents.

Safingol [(2S,3S)-2-amino-1,3-octadecanediol] potentiates the toxicity of doxorubicin (DOX) and cisplatin (CIS) against tumor cells in vitro and in vivo. The present studies were conducted in rats and dogs to evaluate safingol toxicity when administered i.v. as a single agent and to evaluate safingol's ability to potentiate the toxicity of established chemotherapeutic agents to normal tissues in vivo. In an escalating dose study, dogs were administered safingol i.v. at 5, 10, 20, 30, 40, and 75 mg/kg on Days 1 through 6. Necropsies were performed on Day 7. Red urine was observed at 10 mg/kg and higher. Icterus was observed following 40 mg/kg with additional signs of hypoactivity and anorexia occurring after 75 mg/kg. Clinical and microscopic pathology revealed marked hepatotoxicity, venous degeneration and necrosis at injection sites, and evidence of intravascular hemolysis. Doses of 5, 20, or 40 mg safingol/kg were utilized in single i.v. dose rat and dog studies. No evidence of adverse systemic toxicity was seen up to 20 mg/kg in either species [for rats: Cmax = 12,600 (males) or 17,133 (females) ng/ml, AUC = 3853 (males) or 4365 (females) ng x hr/ml; for dogs: Cmax = 2533 ng/ml, AUC = 2851 ng x hr/ml (no sex differences)]. Local effects of venous irritation or intravascular hemolysis were observed at all doses in rats and at 20 and 40 mg/kg in dogs. A dose of 40 mg/kg [for rats: Cmax = 31,233 (males) or 91,300 (females) ng/ml, AUC = 11,519 (males) or 18,620 (females) ng x hr/ml; for dogs: Cmax = 9033 ng/ml, AUC = 11,094 ng x hr/ml (combined sex)] was associated with clinical pathologic and renal histomorphologic changes considered consequent to intravascular hemolysis in both species, lethality and testicular toxicity in rats, and clinical biochemical changes indicative of hepatobiliary injury in dogs. Studies indicated that hemolysis occurred during infusion, was not caused by circulating levels of safingol, and was a function of dose concentration and vein of delivery. Safingol at 10 or 20 mg/kg was administered i.v. to rats 30-60 min prior to myelosuppressive i.v. doses of DOX, CIS, or cyclophosphamide (CYP). Hematology, plus renal function and morphology for CIS-treated animals, was assessed 4 and 14 days later.(ABSTRACT TRUNCATED AT 400 WORDS)

Retroperitoneal actinomycosis.

A 44-year-old man had an abscess involving the left psoas muscle and inferior pole of the left kidney associated with characteristic sulfur granules of actinomycosis. The patient was treated with surgical drainage and debridement and with intensive and prolonged penicillin therapy, resulting in a clinical cure and resolution of both the hydronephrosis and the retroperitoneal mass.